Osteoporosis and its consequence, the osteoporotic fracture, is associated with increasing morbidity in our aging population. Twin studies support the idea of a strong heritable component of this disease, though a search for relevant genetic markers has been inconclusive. In a select group of severely affected middle-aged men with idiopathic osteoporosis, we have described reduced serum levels of insulin-like growth factor I (IGF-I) but normal growth hormone secretion. Since IGH-I is important in osteoblast function and other aspects of bone remodeling, the IGF-I gene appeared a reasonable candidate as a determinant of bone mass. In our cohort of 25 men with idiopathic osteoporosis we have noted a 63% frequency of homozygosity for a specific allele of the IGF-I gene (CC) which represents a polymorphism in CA(n) repeat, 1kb upstream from the IGF-I transcription site. In healthy populations of men and women the frequency of homozygosity for this allele is only 32% (p<0.003). In addition the CC genotype (in both patients and controls) was associated with lower serum IGF-I levels compared to any other genotype, including those with a single C allele (p=0.01). The goal of this project is to study further the IGF-I CC genotype and its relationship to serum IGF-I levels and bone density. We will accomplish this by expanding our male cohort with idiopathic osteoporosis and by recruiting a new cohort of premenopausal women with idiopathic osteoporosis. Family studies of the first degree relatives of these two parallel cohorts will serve as the first step toward linkage analysis of these genotypes and phenotypes